Field of the Invention
[0001] The present invention relates to an active substance-containing polymer gel, and
more particularly it is concerned with an active substance-containing polymer gel
particularly useful for drug delivery systems (DDS).
[0002] The active substance-containing polymer gel according to the present invention may
be used for soft contact lens and DDS for application to ophthalmic mucous membrane
(e.g., trade name "Ocusert", manufactured by FUJISAWA PHARMACEUTICAL CO., LTD. in
Japan) etc. with advantages.
Description of the Prior Art
[0003] In view of its elasticity resembling the living body system, the hydrogel composed
of a polymer of a three-dimensional network structure swelled with an aqueous solvent
has been earnestly investigated for development of medical materials. Representative
embodiments thereof include soft contact lens consisting mainly of polyhydroxyethyl
methacrylate which produces an extremely excellent feeling of insertion (wearing)
due to its elasticity like the living body system.
[0004] Conception of drug delivery system (DDS) was presented around 1970 for establishing
the optimum dose and the best administration process for drugs under consideration
of their pharmacokinetics in the body, and recently researches are being made for
development of more functional DDS in a wide field of technologies.
[0005] An example of process for the control of drug delivery is described in Japanese Patent
Laid-Open SHO 52-56148. In brief, according to the example, polyvinyl alcohol (hereunder
referred to as "PVA") prepared as an aqueous solution or in the state swelled with
water or hydrated gel of crosslinked PVA prepared in advance is treated by radiation
of active rays in the presence of a radical polymerizable monomer which has a electrolyzable
group such as carboxyl group in the form of salt, sulfonate group in the form of salt,
phosphoric acid group in the form of salt, a group of quaternary ammonium salt or
the like, or a polar group such as amino group, carbonyl group, sulfone group, nitro
group, etc. so as to prepare hydrated gel of PVA which has been graft polymerized
with the monomer having an electrolyzable or polar group, after which the gel is impregnated
with an active substance such as drug to provide an active substance-containing polymer
gel. This device aims to retard the delivery of the active substance by incorporating
it into the network structure of the crosslinked PVA to form a weak bond between the
functional groups of the active substance and the electrolyzable or polar groups of
the PVA molecules.
[0006] However, the use of extremely special γ rays as the active rays for the cross-linking
of the starting PVA which is involved in the preparation of the active substance-containing
polymer gel as mentioned above is not general cross-linking means available for use
in usual processes for the preparation of polymer gels. Furthermore, in the above
active substance-containing polymer it is necessary to use an increased dose of γ
rays for the lowered delivery rate of the active substance, and thus in the polymer
gel of the prior art it is impossible to improve the sustained release while keeping
its strength because it tends to reduce the mechanical strength due to the increased
cross-linking density and occurrence of side reactions.
Summary of the Invention
[0007] The present invention has been accomplished to solve the above problems of the prior
art, and it aims to provide an active substance-containing polymer gel which enables
strongly to maintain therein the active substance which has anionic functional groups,
for its significant sustained release and which can be extremely easily formed into
any desired shape.
[0008] The present invention has been completed to attain the above aim. A characteristic
aspect of the present invention resides in an active substance-containing polymer
gel characterized by comprising an active substance having an anionic substituent
held by a copolymer gel through adsorption therein, said copolymer gel being prepared
by copolymerization of a monomer mixture containing at least a hydrocarbon group-containing
(meth)acrylate which has one or more hydroxyl groups and has optionally an intramolecular
ether linkage; and a monomer with a quaternary ammonium salt on the side chain (said
active substance-containing polymer gel being hereunder referred to as "active substance-containing
polymer gel A").
[0009] Another characteristic aspect of the invention is in an active substance-containing
polymer gel characterized by comprising an active substance having an anionic substituent,
held by a copolymer gel prepared through adsorption therein, said copolymer gel being
prepared by copolymerization of a monomer mixture containing at least a hydrocarbon
group-containing (meth)acrylate which has one or more hydroxyl groups and has optionally
an intramolecular ether linkage; a monomer with a quaternary ammonium salt on the
side chain; and an alkyl or a fluoroalkyl group-containing (meth)acrylate (said active
substance-containing polymer gel being hereunder referred to as "active substance-containing
polymer gel B").
Brief Description of the Drawings
[0010]
Fig. 1 is a graph showing the change with time in the rate of the orange II released
from the hydrogels of Examples 1-4 and Comparative Example 1;
Fig. 2 is a graph showing the change with time in the rate of the water-soluble azulene
released from the hydrogels of Examples 5-8 and Comparative Example 2;
Fig. 3 is a graph comparing the change with time in the rate of the DSCG released
from the hydrogels prepared in Examples 1 and 9-10;
Fig. 4 is a graph comparing the change with time in the rate of the DSCG released
from the hydrogels prepared in Examples 1 and 11-12; and
Fig. 5 is a graph comparing the change with time in the rate of the DSCG released
from the hydrogels prepared in Examples 1 and 13-14.
Detailed Description of the Invention
[0011] Both active substance-containing polymer gels A and B according to the present invention
are copolymer gels with an active substance adsorbed therein, and accordingly the
explanation will first be made of the copolymer gel, and then of the active substance.
Copolymer gel
[0012] The hydrocarbon group-containing (meth)acrylate which has one or more hydroxyl groups
and has optionally, an intramolecular ether linkage (said (meth)acrylate being hereunder
referred to as "H(M)A"), which is a monomer constituting the copolymer gel in active
substance-containing polymer gel A according to the present invention, includes 2-hydroxymethyl
(meth)acrylate, 2-hydroxyehtyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 2,3-dihydroxypropyl
(meth)acrylate, 2-polyethyleneglycol monoacrylate, etc., and further a mixture of
two or more thereof. Here, the (meth)acrylate includes both acrylate and methacrylate
throughout the specification. Of them 2-hydroxyethyl methacrylate (hereunder referred
to as "HEMA") is preferable. This is because the workability of a polymer of HEMA
is excellent, and it is easy to adjust the moisture content of the hydrogel prepared
when using it as a comonomer.
[0013] Another monomer which is a component of the copolymer gel constituting active substance-containing
polymer gel A of the present invention, is a monomer with a quaternary salt on the
side chain, which is essential to attain a significant sustained release effect due
to strong holding of the anionic group-having active substance to the hydrogel by
the ionic interaction between the anionic group in the active substance and the quaternary
ammonium ion in the hydrogel.
[0014] As the monomer with a quaternary ammonium salt on the side chain which is used for
the preparation of active substance-containing polymer gel A of the present invention
(said monomer being hereunder referred to as "tert-Am monomer"), preferred are a vinylbenzyl
trialkyl ammonium salt represented by the following general formula (I) or ethyl (meth)acrylate
represented by the following general formula (II):

In the above general formulae (I) and (II), X is a hydrogen atom or a methyl group,
R₁ is a C₅-C₁₂ alkyl group, R₂ and R₃ are the same or different C₁-C₂ alkyl groups,
or R₁, R₂ and R₃ are the same or different C₁-C₄ alkyl groups. That is, among the
three alkyl groups in the general formulae (I) and (II), when one is a long chain
alkyl group of 5-12 carbon atoms, then the other two must be very short alkyl groups
of 1 or 2 carbon atoms, whereas, all the three alkyl groups may have 1-4 carbon atoms,
respectively, if they are very short alkyl groups each consisting of 4 or less carbon
atoms.
[0015] Illustrative embodiments of the vinylbenzyl trialkyl ammonium salt represented by
the general formula (I) are, e.g., vinylbenzyl trimethyl ammonium salt (particularly
ammonium chloride), vinylbenzyl triethyl ammonium salt (particularly ammonium chloride),
vinylbenzyl dimethyl ethyl ammonium salt (particularly ammonium chloride), vinylbenzyl
dimethyl isopropyl ammonium salt (particularly ammonium chloride), vinylbenzyl n-butyl
dimethyl ammonium salt (particularly ammonium chloride), vinylbenzyl dimethyl pentyl
ammonium salt (particularly ammonium chloride), etc.
[0016] Ethyl (meth)acrylate represented by the general formula (II) includes, for example,
2-methacryloxyethyl trimethyl ammonium salt (particularly ammonium chloride), 2-methacryloxyethyl
dimethyl ethyl ammonium salt (particularly ammonium chloride), 2-methacryloxyethyl
dimethyl n-pentyl ammonium salt (particularly ammonium chloride), 2-acryloylethyl
trimethyl ammonium salt (particularly ammonium chloride), 2-acryloylethyl dimethyl
ethyl ammonium salt (particularly ammonium chloride), 2-acryloylethyl triethyl ammonium
salt (particularly ammonium chloride), 2-acryloylethyl dimethyl n-pentyl ammonium
salt (particularly ammonium chloride), etc.
[0017] The amounts of H(M)A and tert-Am monomers to be used is preferably in the range of
0.001≦F≦0.05 wherein the monomer composition ratio

, [C] = the molar concentration of tert-Am monomer, and [H] = the molar concentration
of H(M)A. Most preferred is 0.005≦F≦0.02. At ratios below 0.001 the amount of the
active substance to be held is too small due to the short supply of [C] with respect
to [H] in the hydrogel, whereas the mechanical strength may lower at ratios over 0.05.
[0018] A crosslinkable monomer may be used as a component of the copolymer gel together
with the above mentioned essential components for the preparation of active substance-containing
polymer gel A according to the present invention. The purpose of the use of the crosslinkable
monomer is to facilitate the formation of the network structure of the hydrogel and
to improve of the mechanical strength of the gel, and embodiments thereof include
bismethylene acrylamide, ethylene glycol dimethacrylate (hereunder abbreviated to
EDMA), 2-hydroxy-1,3-dimethacryloxypropane, trimethylolpropane triacrylate, etc. The
amount of the crosslinkable monomer to be used is preferred to be 0.1-10 mol% of the
total monomers. Most preferable is 0.1-3 mol%.
[0019] At less than 0.1 mol % the shortage of the crosslinkable monomer tends to cause poor
form retention of the hydrogel, while in case of the amount exceeding 10 mol%, increased
crosslinked points may cause brittleness of the gel which leads to its lowered mechanical
strength, resulting in poor mechanical processability in some cases.
[0020] As optional components of the copolymer gel of active substance-containing polymer
gel A, a hydrophilic monomer and/or a hydrophobic monomer may be used. The hydrophilic
and hydrophobic monomers have an effect to adjust the moisture content of the resulting
hydrogel, and further serve to adjust the amount of the active substance to be adsorbed
in the hydrogel.
[0021] As the hydrophilic monomer any one is available for use which has biocompatibility
and excellent compatibility with H(M)A and tert-Am monomer, and preferable embodiments
thereof include, for example, N,N-dimethylacrylamide, N,N-dimethylmethacrylamide,
vinylpyrrolidone, etc.
[0022] Also as the hydrophobic monomer any one is available for use which has biocompatibility
and excellent compatibility with H(M)A and tert-Am monomer, and preferably is, e.g.,
methacrylic acid, methyl methacrylate, isobutyl methacrylate, 2,2,2-trifluoroethyl
methacrylate or the like.
[0023] As mentioned above, in the copolymer gel used in the active substance-containing
polymer gel A, H(M)A and tert-Am monomer are essential components, and a hydrophilic
monomer and/or a hydrophobic monomer are optional components of the copolymer gel.
On the other hand, the copolymer gel constituting active substance-containing polymer
gel B is different from that of active substance-containing polymer A only in that
the former contains another essential (meth)acrylate having an alkyl group or a fluoroalkyl
group in addition to H(M)A and tert-Am monomers discussed above. Therefore, further
explanation will now be given with reference only to the (meth)acrylate having an
alkyl group or fluoroalkyl group.
[0024] The (meth)acrylate having an alkyl group or a fluoroalkyl group, which is a monomer
component constituting the copolymer gel composing the active substance-containing
polymer gel B according to the present invention, has functions of adjusting the swelling
coefficient and water content of the hydrogel and of controlling the release rate
of the active substance with an anionic substituent. The (meth)acrylate having an
alkyl or a fluoroalkyl group (hereunder referred to as R(M)A) is preferred to be one
represented by the following general formula (III).

In the above general formula (III), R₄ is a methyl group or a hydrogen atom, and
R₅ is a hydrogen atom or a C₁-C₁₂ alkyl group which may be substituted with fluorine
atom(s).
[0025] Concretely, the R(M)A represented by the general formula (III) includes, for instance,
methacrylic acid, methyl (meth)acrylate, ethyl (meth)acrylate, n-propyl (meth) acrylate,
isopropyl (meth)acrylate, n-butyl (meth)acrylate, isobutyl (meth)acrylate, tert-butyl
(meth)acrylate, n-hexyl (meth)acrylate, n-octyl (meth)acrylate, n-heptyl (meth) acrylate,
n-nonyl (meth)acrylate, 2,2,2-trifluoroethyl (meth)acrylate, 2,2,3,3-tetrafluoropropyl
(meth)acrylate, 2,2,3,3,3-pentafluoropropyl (meth)acrylate, 1,1,1,3,3,3-hexafluoroisopropyl
(meth)acrylate, etc.
[0026] The amount of R(M)A to be added is preferably 1-30 mol% of the total monomers. Most
preferably is 3-25 mol%. At a proportion less than 1 mol %, the release rate of the
active substance which has an anionic substituent cannot be controlled due to shortage
of R(M)A. On the other hand, in some cases, the swelling coefficient and water content
of the hydrogel decrease remarkably at a proportion more than 30 mol%, and accordingly
the anionic substituent-containing active substance may become hard to be released.
[0027] The H(M)A, R(M)A and tert-Am monomer referred to above are desirably used in such
amounts as to satisfy 0.001≦F≦0.1 wherein the monomer composition ratio

, and [C], [H] and [R] signify the molar concentrations of tert-Am monomer, H(M)A
and R(M)A, respectively. Particularly preferred is 0.005≦F≦0.05. At values less than
0.001, [C] comes short for [H] and [R] in the hydrogel, leading to a decreased amount
of the active substance held thereby. On the other hand the mechanical strength of
the resulting hydrogel may lower at values over 0.1.
[0028] Next, explanation will be given regarding the active substance in connection with
active substance-containing polymer gels A and B according to the present invention.
Active substance
[0029] The active substance held in the copolymer gel mentioned above via adsorption includes
any one having an anionic substituent selected from those having an intramolecular
carboxylic acid group, sulforic acid group, phenolic hydroxy group or a salt thereof.
Illustrative embodiments of the active substance which produces a satisfactory pharmacological
effect when the polymer gel is used for an ophthalmic application, for example, disodium
prednisolone-21-phosphate, disodium dexamethasone-21-phosphate, dexamethasone-21-metasulfobenzoate
sodium salt, sodium dexamethasone-21-sulfate (adrenal cortical hormone preparation),
sodium sulbenicillin, sodium carbenicillin (antibiotic), dipotassium glycyrrhizinate,
sodium guaiazulenesulfonate (nonsteroidal anti-inflammatory agent), disodium cromoglycate
(antiallergic agent), glutathione, Catalin (a remedy for cataract), N-acetylcysteine
(an accelerator for cornea cure), etc.
[0030] Active substance-containing polymer gels A and B of the present invention may be
utilized in various uses in addition to the ophthalmic application. Such uses include
various drug delivery systems (DDS), bactericidal sheet, insecticidal sheet, fomentation
and so on, and the active substance is selected appropriately depending on the intended
use.
[0031] As an example of using the active substance-containing polymer gel of the present
invention, when it is intended to use for an ophthalmic application, e.g., a contact
lens, wearing of a soft contact lens made of the active substance-containing polymer
gel of the present invention impregnated with an anti-inflammatory agent or the like
over the eye will be expected to cure the eye if the eye suffers from inflammation,
etc.
[0032] In the other fields of medicine, a plaster impregnated with glyceryl trinitrate,
a remedy for angina pectoris; and a plaster impregnated with scopolamine, a motion
sickness-preventing medicine, etc. are well known and have been put to practical use.
In addition, plasters have become the targets of earnest investigation which enable
the supply of an medicine at a constant concentration which is hard to be kept at
a constant blood concentration via oral administration, such as one for diabetes mellitus,
elevated blood pressure, climacteric disturbance or the like and further a sudden
increase in the blood concentration of which may involve some risk to the patient.
[0033] The active substance-containing polymer gel of the present invention is extremely
useful for the production of "percutaneous preparations" intended for administration
of drugs expected to be released gradually as mentioned above.
[0034] Meanwhile, in domestic closets, etc. molds are apt to grow due to moisture or the
like, and also insects tend to grow which live on the fibers of clothes. As means
to prevent the growth of such molds and insects over a long period of time now commercially
available are sheets impregnated with fungicidal or insecticidal agents, which have
become to be usually used for various purposes.
[0035] Even fungicides and insecticides may have a bad influence upon or are even poisonous
to humans if they are present at high concentrations in the air, but this problem
is overcome by enclosing them in an active substance-containing polymer gel according
to the present invention which releases them little by little, thereby providing a
prolonged fungicidal or insecticidal effect at a concentration in the air which is
safe to humans.
[0036] As mentioned above, the active substance-containing polymer gels provided by the
present invention may be applied to various cases in daily life as well.
[0037] A further explanation will now be made regarding processes for the preparation of
active substance-containing polymer gels A and B of the present invention with reference
to the case of an ophthalmic application.
[0038] For the preparation of a hydrogel for an ophthalmic application, first a polymerization
initiator is added to the mixtures of the monomers mentioned above which is then stirred
well to produce a homogenous solution of the monomer mixture.
[0039] Here, the radical initiator available for use may be any conventional one, for example,
a peroxide such as lauroyl peroxide, cumene hydroperoxide, benzoyl peroxide or the
like, azobisvaleronitrile or azobisisobutylonitrile (hereunder abbreviated to AIBN),
of which desirable is AIBN. The amount of the initiator to be used is preferred to
be in the order of 0.02-0.5 mol% of the total monomers.
[0040] Next, the above mixture solution is placed in a metal, glass or plastic container
of any desired shape, sealed and heated stepwise or continuously to a temperature
range of 25-120°C in a thermostat, etc. for the completion of polymerization in 12-120
hours. The polymerization may also be accomplished by photo-polymerization with ultraviolet
rays, visible rays or the like. Further, the above monomer mixture solution may be
mixed with an organic solvent for solution polymerization. Desired embodiments of
the organic solvent include, for example, methanol, ethanol, acetone, etc.
[0041] After polymerization, the mixture is cooled to room temperature, and the polymerization
product is cut and polished to obtain a desired shape. The desired shape is, for example,
an approximate form of the conventional contact lens or any other ophthalmic insertable
products, film form, sheet form, etc. In addition, the cutting and polishing become
unnecessary if the polymerization procedure is carried out in a container having the
corresponding shape to a shape of a contact lens.
[0042] Thereafter, the polymerization product having a desired shape is hydrated for swelling
to obtain a hydrogel. The liquid to be used for hydration to swelling (hereunder referred
to as "hydration liquid") is, for example, water, physiologic saline, isotonic buffer
solution or the like. The hydration liquid is heated for immersion of the above polymerization
product therein under conditions of a temperature of 60-100°C and the ambient pressure,
upon which the product rapidly undergoes a change into hydrated, swelled state.
[0043] The above treatment for hydration to swelling may simultaneously remove the residual
monomers remaining in the polymerization product.
[0044] Next, a solution of an active substance with an anionic substituent is prepared in
advance, into which the above hydrogel is immersed to impregnate the latter with the
active substance, thereby providing a hydrogel in which an active substance is adsorbed
therein.
[0045] The solvent available for dissolving the above active substance is water, hydrophilic
solvent or a mixed solvent of water and a hydrophilic solvent. Here, the hydrophilic
solvent includes an alcohol such as methanol, ethanol, isopropanol or n-butanol, dimethylsulfoxide
or the like, while the mixed solvent of water and a hydrophilic solvent includes one
of water and an alcohol or water and dimethylsulfoxide or the like.
[0046] The concentration of the active substance to be contained in the above solution is
determined appropriately depending on the respective active substances in consideration
of the solubility of the active substance, its minimum effective concentration required
for producing the expected pharmaceutical efficacy, its maximum safety concentration,
etc., and usually a concentration of 1.0 x 10⁻⁶ (mol/l) to 1.0 x 10⁻²(mole/l) is preferred.
Examples
[0047] The present invention will now be explained in more detail with reference to the
Examples, without limiting it thereto.
Example 1 (Active substance-containing polymer gel A)
[0048] In a 50 ml ampoule there were placed 32.2 g (0.247 mol) of HEMA, 0.53 g (0.0025 mol)
of a vinyl benzyl trimethyl ammonium salt (hereunder abbrev. as QBm), 0.25 g (0.5
mol% of the total monomers) of EDMA, and 0.033 g (0.08 mol% of the total monomers)
of AIBN, and the mixture was stirred for 1 hour in a nitrogen atmosphere. Here, the
monomer composition ratio F was 0.01.
[0049] After the stirring, the mixture was transferred to a polyethylene container (d.:
15 mm, h.: 17 mm), and then subjected to polymerization at 50-100°C for 72 hours.
The resulting polymer was taken out of the container and cut into flat disks with
a diameter of 13 mm and a thickness of 0.5 mm, after which the surface was polished
to provide flat transparent disks. The disks were immersed in distilled water at 80°C
for 2 hours for swelling due to hydration, thereby producing a hydrogel from which
the residual monomers were removed.
[0050] To 10 ml of a 20% aqueous solution of ethanol was added 0.35 mg (1 x 10⁻⁶ mol) of
sodium 4-[(2-hydroxy-1-naphthalyl)azo]-benzenesulfonate (another name: acid orange
7; hereunder abbrev. to orange II), a dye comprising a sulfonate ion used as the test
substance, and then the mixture was stirred to prepare 10 ml of a solution of orange
II in ethanol. The hydrogel was placed in the orange II solution for a 24 hours immersion
at 25°C to adsorb the orange II in the hydrogel. Thereafter, the hydrogel with the
orange II adsorbed therein was immersed into 50 ml of distilled water at 25°C for
48 hours to replace the ethanol by the distilled water while releasing the free orange
II not combined with the cations in the hydrogel.
Measurement of the amount of the orange II adsorbed in the hydrogel
[0051] As mentioned above, the hydrogel was immersed in 10 ml of a solution of orange II
in ethanol (1.0 x 10⁻⁴ mol/l) for 24 hours; and the adsorption was confirmed to have
attained the equilibrium. Thereafter, in order to measure the amount of the orange
II adsorbed in the hydrogel, measurement of light absorption at a wavelength of 486.6
nm was made of the residual solution of orange II in ethanol after the 24 hours immersion
(liquid A) and of the distilled water which contained the free orange II released
from the orange II-containing hydrogel after immersing in distilled water for 48 hours
(liquid B), to determine the orange II content each of the liquids A and B. The difference
was calculated to determine the amount of the orange II combined with the cations
in the above hydrogel. The spectrophotometer used was Model U-3210 of Hitachi Ltd.
in Japan .
[0052] In this example, the amount of the orange II adsorbed in the hydrogel was 0.106 x
10⁻⁴ (mol/g of polymer).
Change with time in the amount of the orange II released from the hydrogel adsorbing
orange II therein
[0053] The hydrogel which was subjected to measurement of the amount of the orange II adsorbed
as mentioned above was immersed in 20 ml of physiological saline at 37°C, after which
samples of the immersion solution were taken at various intervals (1, 2, 3, 4, 5,
24, 48 and 72 hours), the light absorption at a wavelength of 486.8 nm was measured
of each of the samples to determine the orange II content of the immersion solution.
Thus, the total amount of orange II released from the hydrogel (accumulated amount
of the orange II released) was measured, and percentage for the above amount of the
orange II adsorbed was determined as the rate of the orange II released from the hydrogel.
[0054] The rate of the orange II released from the hydrogel was the following.
Time elapsed |
Release rate |
1 hr. |
5.1% |
2 hrs. |
9.3% |
3 hrs. |
12.9% |
4 hrs. |
16.6% |
5 hrs. |
18.9% |
24 hrs. |
44.1% |
48 hrs. |
61.8% |
72 hrs. |
78.1% |
Examples 2-4 (Active substance-containing polymer gel A)
[0055] In the same manner as in Example 1, AIBN was added to monomer mixtures comprising
HEMA, QBm and EDMA and the resulting mixtures were subjected to radical polymerization.
Thus produced polymers were swelled by hydration to provide the hydrogels of Examples
2-4. The amounts of the monomers, cross-linking monomer and radical polymerization
initiator are listed in Table 1.
[0056] Thereafter, the resulting hydrogels were subjected to the same treatment as in Example
1 to adsorb orange II in the hydrogels of the respective examples, and then the free
orange II not combined with the cations in the hydrogels was eliminated.
[0057] Similarly in Example 1, measurement was made of the amount of the orange II adsorbed
in the respective hydrogels and of the total amount of the orange II released from
the respective hydrogels.
[0058] Table 2 shows the result of measurement of the amount of orange II adsorbed in the
respective hydrogels.
[0059] Also the change with time in the rate of the orange II released from each hydrogel
is shown in Fig. 1.
Comparative Example 1
[0060] In a 50 ml ampoule there were placed 30.2 g (0.238 mol ) of HEMA, 0.25 g (0.5 mol%
of the total monomers) of EDMA, and 0.033 g (0.08 mol% of the total monomers) of AIBN,
and the mixture was stirred for 1 hour in a nitrogen atmosphere. After the stirring
the mixture was treated in the same manner as in Example 1 to prepare the hydrogel
of Comparative Example 1. Thereafter, the hydrogel was subjected to the same treatment
as in Example 1 to adsorb orange II in the hydrogel, and then the free orange II not
combined with the cations in the hydrogel was eliminated.
[0061] Similarly in Example 1, measurement was made of the amount of the orange II adsorbed
in the hydrogel and of the total amount of the orange II released from the hydrogel.
[0062] Table 2 shows the result of measurement of the amount of the orange II adsorbed in
the hydrogel.
[0063] Also the change with time in the rate of the orange II released from the hydrogel
is shown in Fig. 1.

[0064] As shown in Table 2, compared with the results of Comparative Example 1, each of
the hydrogels of Examples 1-4 adsorbed more active substance, orange II.
[0065] In Comparative Example 1, the amount of the orange II adsorbed in the hydrogel was
as small as 0.492 x 10⁻⁷ (mol/g of polymer), and completely no release was observed
in physiological saline as shown by the release rate curve of Fig. 1.
[0066] In contrast, significant sustained release was observed in all of the Examples 1-4
over a long period of time in order of 72 hours.
[0067] This significant sustained release as shown in Fig. 1 is believed to have resulted
from the presence of the bonding due to the electrostatic interaction between the
ammonium groups in the hydrogels and orange II.
Example 5 (Active substance-containing polymer gel A)
[0068] In the same manner as in Example 1, AIBN was added to a monomer mixture comprising
HEMA, QBm and EDMA and the resulting mixture was subjected to radical polymerization.
Thus produced polymer was swelled by hydration to provide the hydrogel of Example
5. The amounts of the monomers, cross-linking monomer and radical polymerization initiator
are listed in Table 3. Next, to 10 ml of distilled water was added 3.2 mg (1 x 10⁻⁵
mol) of sodium guaiazulenesulfonate (hereunder abbrev. to water-soluble azulene),
and in 10 ml of the resulting aqueous solution of the water-soluble azulene (1.0 x
10⁻³ (mol/l)) was immersed the above mentioned gel at 25°C for 24 hours to adsorb
the water-soluble azulene in the hydrogel. Thereafter, the hydrogel with the water-soluble
azulene adsorbed therein was immersed in 50 ml of distilled water at 25°C for 48 hours
to eliminate the free water-soluble azulene not combined with the cations in the hydrogel.
Measurement of the amount of the water-soluble azulene adsorbed in the hydrogel
[0069] As mentioned above, the hydrogel was immersed in 10 ml of a solution of water-soluble
azulene in ethanol (1.0 x 10⁻³ mol/l) for 24 hours; and the adsorption was confirmed
to have attained the equilibrium. Thereafter, in order to measure the amount of the
water-soluble azulene adsorbed in the hydrogel, measurement of light absorption at
a wavelength of 486.6 nm was made of the residual solution of the water-soluble azulene
in ethanol after the 24 hour immersion (liquid C) and of the distilled water which
contained the free water-soluble azulene released from the water-soluble azulene-containing
hydrogel after immersing in the distilled water for 48 hours (liquid D), to determine
the water-soluble azulene content each of the liquids C and D. The difference was
calculated to determine the amount of the water-soluble azulene combined with the
cations in the above hydrogel. The spectrophotometer used was Model U-3210 of Hitachi
Ltd. in Japan .
[0070] The amount of the water-soluble azulene adsorbed in the hydrogel of this example
was 0.343 x 10⁻⁴ (mol/g of polymer).
Change with time in the amount of the water-soluble azulene released from the hydrogel
adsorbing water-soluble azulene therein
[0071] The hydrogel which was subjected to measurement of the amount of the water-soluble
azulene adsorbed as mentioned above was immersed in 20 ml of physiological saline
at 37°C, after which samples of the immersion solution were taken at various intervals
(1, 2, 3, 4, 5, 24, 48 and 72 hours), the light absorption at a wavelength of 292.8
nm was measured of each of the samples to determine the water-soluble azulene content
of the immersion solution. Thus the total amount of water-soluble azulene released
from the hydrogel (accumulated release amount) was measured , and percentage for the
above amount adsorbed was determined as the rate of the water-soluble azulene released
from the hydrogel.
[0072] The rate of the water-soluble azulene released from the hydrogel was the following.
Time elapsed |
Release rate |
1 hr. |
16.3% |
2 hrs. |
28.9% |
3 hrs. |
38.4% |
4 hrs. |
45.7% |
5 hrs. |
53.1% |
24 hrs. |
82.6% |
48 hrs. |
92.6% |
72 hrs. |
95.4% |
Examples 6-8 (Active substance-containing polymer gel A)
[0073] In the same manner as in Example 1, AIBN was added to monomer mixtures comprising
HEMA, QBm and EDMA and the resulting mixtures were subjected to radical polymerization.
Thus produced polymers were swelled by hydration to provide the respective hydrogels
of Examples 6-8. The amounts of the monomers, cross-linking monomer and radical polymerization
initiator are listed in Table 3.
[0074] Thereafter, the resulting hydrogels were subjected to the same treatment as in Example
5 to adsorb the water-soluble azulene in the hydrogels of the respective examples,
and then the free water-soluble azulene not combined with the cations in the hydrogels
was eliminated.
[0075] Similarly in Example 5, measurement was made of the amount of the water-soluble azulene
adsorbed in the respective hydrogels and of the total amount of the water-soluble
azulene released from the respective hydrogels.
[0076] Table 4 shows the result of measurement of the amount of the water-soluble azulene
adsorbed in the respective hydrogels.
[0077] Also the change with time in the rate of the water-soluble azulene released from
each hydrogel is shown in Fig. 2.
Comparative Example 2
[0078] In a 50 ml ampoule there were placed 30.2 g (0.238 mol ) of HEMA, 0.25 g (0.5 mol
% of the total monomers) of EDMA, and 0.033 g (0.087 mol % of the total monomers)
of AIBN, and the mixture was stirred for 1 hour in a nitrogen atmosphere. After the
stirring the mixture was treated in the same manner as in Example 5 to prepare the
hydrogel of Comparative Example 2. Thereafter, the hydrogel was subjected to the same
treatment as in Example 5 to adsorb the water-soluble azulene in the hydrogel, and
then the free water-soluble azulene not combined with the cations in the hydrogel
was eliminated.
[0079] Similarly in Example 5, measurement was made of the amount of the water-soluble azulene
adsorbed in the hydrogel and of the total of the water-soluble azulene released from
the hydrogel.
[0080] Table 4 shows the result of measurement of the amount of the water-soluble azulene
adsorbed in the hydrogel.
[0081] Also the change with time in the rate of the water-soluble azulene released from
the hydrogel is shown in Fig. 2.

[0082] As shown in Table 4, compared with the results of Comparative Example 2, each of
the hydrogels of Examples 5-8 adsorbed more active substance, water-soluble azulene.
[0083] In Comparative Example 2, the amount of the water-soluble azulene adsorbed in the
hydrogel was as small as 0.219 x 10⁻⁵ (mol/g of polymer), and completely no release
was observed in physiological saline as shown by the release rate curve of Fig. 2.
[0084] In contrast, significant sustained release was observed in all the Examples 5-8 over
a long period of time in the order of 72 hours.
[0085] This significant sustained release as shown in Fig. 2 is believed to have resulted
from the presence of the bonding due to the electrostatic interaction between the
ammonium groups in the hydrogels and water-soluble azulene.
Example 9 (Active substance-containing polymer gel B)
[0086] In a 50 ml ampoule there were placed 23.7 g (0.182 mol ) of HEMA, 2 g (0.02 mol )
of methyl methacrylate (hereunder abbrev. to MMA), 0.42 g (0.002 mol ) of vinylbenzyl
trimethyl ammonium salt (hereunder abbrev. as QBm), 0.202 g (0.5 mol % of the total
monomers) of EDMA, and 0.027 g (0.08 mol % of the total monomers) of AIBN, and the
mixture was stirred for 1 hour in a nitrogen atmosphere. Here, the monomeric composition
ratio F was 0.01. After stirring, the mixture was transferred to a polyethylene container
(d.: 15 mm, h.: 17 mm), and then subjected to polymerization at 50-100°C for 72 hours.
The resulting polymer was taken out of the container and cut into flat disks with
a diameter of 13 mm and a thickness of 0.5 mm, after which the surface was polished
to provide flat transparent disks. The disks were immersed in distilled water at 80°C
for 2 hours for swelling due to hydration, thereby producing a hydrogel from which
the residual monomers were removed.
[0087] Separately, 5.12 mg (1 x 10⁻⁵ mol) of disodium cromoglycate (hereunder abbrev. to
DSCG), an active substance, was added to 10 ml of distilled water, followed by mixing
and stirring, to prepare 10 ml of an aqueous solution of DSCG in which the above mentioned
hydrogel was placed for a 24 hours immersion therein at 25°C to adsorb the DSCG in
the hydrogel. Thereafter, the hydrogel with the DSCG adsorbed therein was immersed
into 50 ml of distilled water at 37°C for 48 hours to eliminate the free DSCG not
combined with the cations in the hydrogel.
Measurement of linear swelling coefficient and water content of polymer
[0088] A polymer material having a diameter of 13 mm and a thickness of 0.5 mm when dried
was immersed in distilled water at 20°C for 48 hours; the swelling was confirmed to
have attained the equilibrium. Then measurement of the polymer was made of the diameter
prior to hydration swelling (Dd), that after hydration swelling (Dw), the weight after
hydration swelling (Wω) and that after redrying (Wd), then calculation was made of
the linear swelling coefficient (hereunder referred to as "swelling coefficient")
and the water content.

Measurement of the amount of the DSCG adsorbed in the hydrogel
[0089] As mentioned above, the hydrogel was immersed in 10 ml of an aqueous solution of
DSCG (1.0 x 10⁻³ mol/l) for 24 hours; the adsorption was confirmed to have attained
the equilibrium. Thereafter, in order to measure the amount of the DSCG adsorbed in
the hydrogel, measurement of the light absorption at a wavelength of 239 nm was made
of the residual aqueous solution of DSCG after the 24 hours immersion (liquid A) and
of the distilled water which contained the free DSCG released from the DSCG-adsorbing
hydrogel immersed in distilled water for 48 hours (liquid B) to determine the DSCG
content each of the liquids A and B. The difference was calculated to determine the
amount of the DSCG combined with the cations in the above hydrogel. Here, the spectrophotometer
used was Model U-3210 of Hitachi Ltd. in Japan).
[0090] The amount of the DSCG adsorbed on the hydrogel of this example was 0.218 x 10⁻⁴
(mol/g of polymer).
Change with time in the amount of the DSCG released from the hydrogel adsorbing DSCG
therein
[0091] The hydrogel which was subjected to measurement of the amount of the DSCG adsorbed
as mentioned above was immersed in 20 ml of physiological saline at 37°C, after which
samples of the immersion solution were taken at various intervals (1, 2, 3, 4, 5,
24, 48 and 72 hours), the light absorption at a wavelength of 239 nm was measured
of each of the samples to determine the DSCG content of the immersion solution. Thus
the total amount of DSCG released from the hydrogel (accumulated amount of the DSCG
released) was measured, and percentage for the above amount of the DSCG adsorbed was
determined as the rate of the DSCG released from the hydrogel.
[0092] The release rate of the DSCG released from the hydrogel was the following.
Time elapsed |
Release rate |
1 hr. |
23.2% |
2 hrs. |
31.8% |
3 hrs. |
38.4% |
4 hrs. |
44.6% |
5 hrs. |
49.6% |
24 hrs. |
84.0% |
48 hrs. |
94.1% |
72 hrs. |
97.8% |
Example 10 (Active substance-containing polymer gel B)
[0093] In the same manner as in Example 9, AIBN was added to a monomer mixture comprising
HEMA, MMA and EDMA for radical polymerization. The resulting polymer was swelled by
hydration to provide a hydrogel. The amounts of the monomers, cross-linking monomer
and radical polymerization initiator are listed in Table 5.
[0094] Thereafter, the resulting hydrogel was subjected to the same treatment as in Example
9 to adsorb the DSCG in the hydrogel, and then the free DSCG not combined with the
cations in the hydrogel were eliminated.
[0095] Similarly in Example 9, measurement was made of the amount of the DSCG adsorbed in
the hydrogel and of the total amount of DSCG released from the respective hydrogel.
[0096] Table 2 shows the result of measurement of the swelling coefficient and water content
of the polymer and the amount of the DSCG adsorbed in the hydrogel.
[0097] Also the change with time in the rate of the DSCG released from each hydrogel is
shown in Fig. 3.
Examples 11-12 (Active substance-containing polymer gel B)
[0098] In the same manner as in Example 9, AIBN was added to a monomer mixture comprising
HEMA, n-butyl methacrylate (hereunder abbrev. to BMA), QBm and EDMA for radical polymerization.
The resulting polymer was swelled by hydration to provide the respective hydrogels
of Examples 11-12. The amounts of the monomers, cross-linking monomer and radical
polymerization initiator are listed in Table 5.
[0099] Thereafter, the resulting hydrogels were subjected to the same treatment as in Example
9 to adsorb the DSCG in the hydrogels of the respective examples, and then the free
DSCG not combined with the cations in the hydrogels were eliminated.
[0100] Similarly in Example 9, measurement was made of the amount of the DSCG adsorbed in
the respective hydrogels and of the total amount of DSCG released from the respective
hydrogels.
[0101] Table 6 shows the result of measurement of the swelling coefficient and water content
of the polymers and of the amount of the DSCG adsorbed in the hydrogels.
[0102] Also the change with time in the rate of the DSCG released from each hydrogels is
shown in Fig. 4.
Examples 13-14 (Active substance-containing polymer gel B)
[0103] In the same manner as in Example 9, AIBN was added to a monomer mixture comprising
HEMA, 2,2,2-trifluoroethyl methacrylate (hereunder abbrev. to 3FE), QBm and EDMA for
radical polymerization. The resulting polymer was swelled by hydration to provide
the respective hydrogels of Examples 13-14. The amounts of the monomers, cross-linking
monomer and radical polymerization initiator are listed in Table 5.
[0104] Thereafter, the resulting hydrogels were subjected to the same treatment as in Example
9 to adsorb the DSCG in the hydrogels of the respective examples, and then the free
DSCG not combined with the cations in the hydrogels were eliminated.
[0105] Similarly in Example 9, measurement was made of the amount of the DSCG adsorbed in
the respective hydrogels and of the total amount of DSCG released from the respective
hydrogels.
[0106] Table 6 shows the result of measurement of the swelling coefficient and water content
of the polymers and of the amount of the DSCG adsorbed in the hydrogels.
[0107] Also the change with time in the rate of the DSCG released from each hydrogels is
shown in Fig. 5.

[0108] In the table,
* Mol% of the totalmonomers.
HEMA: 2-hydroxyethyl methacrylate;
MMA: methyl methacrylate;
BMA: n-butyl methacrylate;
3FE: 2,2,2-trifluoroethyl methacrylate;
QBM: vinylbenzyl trimethyl ammonium salt;
EDMA: ethylene glycol dimethacrylate (cross-linking monomer); and
AIBN: azobisisobutyronitrile (radical polymerization initiator).
Table 6
Results of measurement of swelling coefficient, water content and DSCG adsorption
amount of the polymers |
Examples |
Swelling coefficient(%) |
Water content(%) |
DSCG adsorption amount (mol/g of polymer) |
9 |
17.2 |
34.5 |
0.228 x 10⁻⁴ |
10 |
14.3 |
30.1 |
0.219 x 10⁻⁴ |
11 |
15.2 |
31.1 |
0.254 x 10⁻⁴ |
12 |
11.1 |
25.4 |
0.191 x 10⁻⁴ |
13 |
15.5 |
32.0 |
0.245 x 10⁻⁴ |
14 |
12.1 |
25.7 |
0.191 x 10⁻⁴ |
1 |
21.1 |
39.1 |
0.198 x 10⁻⁴ |
[0109] In the table, DSCG represents disodium cromoglycate (active substance).
[0110] As shown in Table 6, compared with active substance-containing polymer gel A of Example
1, almost no difference in the DSCG adsorption amount was found for the active substance-containing
polymer gel B of Examples 9-14, though all of them underwent lowered swelling coefficient
and water content.
[0111] Relating to the hydrogel of Example 1, most of the DSCG adsorbed in the hydrogel
was released in 24 hours as shown by the release rate curves in Figs. 3-5.
[0112] In contrast, significant sustained release was observed in all the Examples 9-14
over a long period of time in the order of 72 hours.
[0113] This significant sustained release as shown in Figs. 3-5 is believed to have resulted
from the introduction of R(M)A into the hydrogels thereby reducing the diffusion rate
of the DSCG in the hydrogels.
[0114] As mentioned above, according to the present invention it is possible to produce
active substance-containing polymer gel A capable of strongly holding an anionic functional
group-containing active substance therein to produce a significant sustained release
effect and of being worked into any desired form in an extremely easy manner.
[0115] Also according to the present invention it is possible to produce active substance-containing
polymer gel B capable of strongly holding an anionic functional group-having active
substance therein to produce a significant sustained release effect by controlling
the swelling coefficient and water content of the hydrogel.
[0116] Accordingly, active substance-containing polymer gels A and B of the present invention
may be employed for the preparation of various drug delivery systems (DDS), fungicidal
sheets, insecticidal sheets, fomentation, etc with advantages, and particularly preferably
for the preparation of ophthalmic insertions.